Our primary research interests are the study of the genes that are altered in cancer and the cellular pathways these genes perturb. Identifying the genetic alterations and understanding how they work provides the foundation for novel approaches to the prevention, diagnosis and treatment of cancer. To fulfill these goals, we are using a sequence-based mutational analysis to evaluate genetic alterations in cutaneous malignant melanoma. Melanoma develops from the malignant transformation of melanocytes. It is the most common fatal skin cancer, and its incidence has increased at a more rapid rate than any other malignancy in the US. Unlike early-stage disease, late stage melanoma has no effective treatment;hence our studies focus on late stage disease. The clinical progression is assumed to correspond to the accumulation of genetic mutations. In order to develop treatments for advanced disease, it is important to understand the genetic alterations leading to melanoma as such understanding will permit personalized design of treatments for melanoma. For this project, we have started to establish a tumor bank, which we use as a source of genomic DNA. In order to determine the quality of the tumor bank a few strategies have been employed: a. Cytopatholgy is used to determine the percentage of melanoma cells within the sample provided. Only samples that include at least 75% melanoma-derived cells qualify, to ensure that non-neoplastic cells within the tumors do not complicate the analysis. b. To verify that we can detect mutations in tumor DNA, we sequence commonly known oncogenic mutations in metastatic melanoma such BRAF and NRAS. Using 80 samples from our tumor bank we have discovered novel mutations in the transcription factor MITF, in matrix metalloproteinase genes including MMP-8 as well as in protein tyrosine kinases such as ERBB4. As the mutations occur in discreet functional domains and the affected residues within these clusters are highly conserved evolutionarily it is expected that these mutations are functionally important. These results have been pursued using several avenues: a. The discovered mutations were cloned and were found to have functional effects. b. We are preparing to conduct a clinical trial based on mutations found in melanoma patients and treatment with mutation-specific drugs. Our work provides a strong rationale for development of therapeutic and diagnostic approaches for individuals harboring the various discovered mutations. Using these tools, one could envision tailored therapeutics based on the mutations in an individuals cancer.